SUMMARY

• Please refer to the local labeling for relevant information on post-infusion monitoring of CARVYKTI.¹
• Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction.¹
• Monitor patients at least daily for 10 days following CARVYKTI infusion at a risk evaluation and mitigation strategy (REMS)-certified healthcare facility for signs and symptoms of cytokine release syndrome (CRS) and neurologic toxicities. Monitor periodically for 4 weeks for signs and symptoms of delayed neurologic toxicity.¹
• Instruct patients to remain within proximity of a REMS-certified healthcare facility for at least 4 weeks following infusion.¹
• CARTITUDE-1 (MMY2001) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated CARVYKTI in patients with relapsed/refractory multiple myeloma (RRMM) who had previously received a proteasome inhibitor (PI), an immunomodulatory agent, and an anti-cluster of differentiation 38 (CD38) antibody.^2-4
  • Per protocol, patients were closely monitored for safety and disease assessments during the post-infusion period (day 1-100 after administration of CARVYKTI). During the post-treatment period (from day 101 to study completion), safety and disease assessments were conducted every 28 days.²
• CARTITUDE-4 (MMY3002) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of pomalidomide, bortezomib, and dexamethasone [PVd] or DARZALEX FASPRO [daratumumab and hyaluronidase], pomalidomide, and dexamethasone [DPd]) in adult patients with lenalidomide-refractory multiple myeloma (MM) after 1-3 prior line of therapy (LOT).^5,6
  • Per protocol, patients were closely monitored for safety and disease assessments during the post-infusion period (day 1-112 after administration of CARVYKTI). During the post-treatment period (once the post-infusion follow-up is complete on day 112 to the end of the study [defined until approximately 250 deaths have occurred]), safety and disease assessments were conducted every 28 days.⁷

PRODUCT LABELING

Prescribing Information

• CARVYKTI (ciltacabtagene autoleucel) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;http://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/CARVYKTI-pi.pdf.
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.

Administration

Monitoring After Infusion

• Administer CARVYKTI at a REMS-certified healthcare facility.¹
• Monitor patients at least daily for 10 days following CARVYKTI infusion at a certified healthcare facility for signs and symptoms of CRS and neurologic toxicities. Monitor periodically for 4 weeks for signs and symptoms of delayed neurologic toxicity.¹
• Instruct patients to remain within proximity of a certified healthcare facility for at least 4 weeks following infusion.¹
• Instruct patients to refrain from driving or hazardous activities for at least 8 weeks following infusion.¹

Warnings and Precautions

Cytokine Release Syndrome

• CRS, including fatal or life-threatening reactions, occurred following treatment with CARVYKTI.¹
• Among patients receiving CARVYKTI for relapsed or refractory multiple myeloma in the CARTITUDE-1 and CARTITUDE-4 studies (N=285), CRS occurred in 84% (238/285), including grade ≥3 CRS in 4% (11/285) of patients.¹
• The median time to onset of CRS, any grade, was 7 days (range, 1-23 days). CRS resolved in 82% with a median duration of 4 days (range, 1-97 days).¹
• Serious events that may be associated with CRS include pyrexia, hemophagocytic lymphohistiocytosis (HLH), respiratory failure, disseminated intravascular coagulation, capillary leak syndrome, and supraventricular and ventricular tachycardia.¹
• CRS occurred in 78% of patients in CARTITUDE-4 (3% grade 3 to 4) and in 95% of patients in CARTITUDE-1 (4% grade 3 to 4).¹
• Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension. CRS has been reported to be associated with findings of HLH/macrophage activation syndrome (MAS), and the physiology of the syndromes may overlap. HLH/MAS is a potentially life-threatening condition. In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS.¹
• Ensure that a minimum of two doses of tocilizumab are available prior to infusion of CARVYKTI.¹
• Monitor patients at least daily for 10 days following CARVYKTI infusion at a REMScertified healthcare facility for signs and symptoms of CRS. Monitor patients for signs or symptoms of CRS for at least 4 weeks after infusion. At the first sign of CRS, immediately institute treatment with supportive care, tocilizumab, or tocilizumab and corticosteroids as indicated in Table 1 of Prescribing Information.¹
• Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.¹

Neurologic Toxicities

• Neurologic toxicities, which may be severe, life-threatening or fatal, occurred following treatment with CARVYKTI. Neurologic toxicities included immune effector cell-associated neurotoxicity syndrome (ICANS), neurologic toxicity with signs and symptoms of parkinsonism, Guillain-Barré syndrome (GBS), immune mediated myelitis, peripheral neuropathies and cranial nerve palsies. Counsel patients on the signs and symptoms of these neurologic toxicities, and on the delayed nature of onset of some of these toxicities. Instruct patients to seek immediate medical attention for further assessment and management if signs or symptoms of any of these neurologic toxicities occur at any time.¹
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies for relapsed and refractory multiple myeloma, one or more neurologic toxicities occurred in 24% (69/285), including grade ≥3 cases in 7% (19/285) of patients.¹
• The median time to onset was 10 days (range, 1-101 days) with 63/69 (91%) of cases developing by 30 days.¹
• Neurologic toxicities resolved in 72% (50/69) of patients with a median duration to resolution of 23 days (range, 1-544 days).¹

Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

• Patients receiving CARVYKTI may experience fatal or life-threatening ICANS following treatment with CARVYKTI, including before CRS onset, concurrently with CRS, after CRS resolution, or in the absence of CRS.¹
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, ICANS occurred in 13% (36/285), including grade ≥3 in 2% (6/285) of the patients.¹
• ICANS occurred in 7% of patients in CARTITUDE-4 (Grade 3, 0.5%) and in 23% of patients in CARTITUDE-1 (Grade 3, 3%).¹
• The median time to onset of ICANS was 8 days (range, 1-28 days). ICANS resolved in 30 of 36 (83%) patients with a median time to resolution of 3 days (range, 1-143 days).¹
• The median duration of ICANS was 6 days (range, 1-1229) in all patients including those with ongoing neurologic events at the time of death or data cut off.¹
• Monitor patients at least daily for 10 days following CARVYKTI infusion at the REMS-certified healthcare facility for signs and symptoms of ICANS. Rule out other causes of ICANS symptoms. Monitor patients for signs or symptoms of ICANS for at least 4 weeks after infusion and treat promptly. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.¹

Parkinsonism

• Neurologic toxicity with parkinsonism has been reported in clinical trials of CARVYKTI.¹
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, parkinsonism occurred in 3% (8/285), including grade ≥3 in 2% (5/285) of the patients.¹
• Parkinsonism occurred in 1% of patients in CARTITUDE-4 (no Grade 3 to 4) and in 6% of patients in CARTITUDE-1 (Grade 3 to 4, 4%).¹
• The median time to onset of parkinsonism was 56 days (range, 14-914 days).¹
• Parkinsonism resolved in 1 of 8 (13%) of patients with a median time to resolution of 523 days.¹
• The median duration of parkinsonism was 243.5 days (range, 62-720 days) in all patients including those with ongoing neurologic events at the time of death or data cut off.¹
• Monitor patients for signs and symptoms of parkinsonism that may be delayed in onset and managed with supportive care measures. There is limited efficacy information with medications used for the treatment of Parkinson’s disease for the improvement or resolution of parkinsonism symptoms following CARVYKTI treatment.¹
• The manifestations of parkinsonism included movement disorders, cognitive impairment, and personality changes.¹

Guillain-Barré Syndrome (GBS)

• A fatal outcome following GBS occurred following treatment with CARVYKTI despite treatment with intravenous immunoglobulins (IVIGs). Symptoms reported include those consistent with Miller-Fisher variant of GBS, encephalopathy, motor weakness, speech disturbances, and polyradiculoneuritis.¹
• Monitor for GBS. Evaluate patients presenting with peripheral neuropathy for GBS. Consider treatment of GBS with supportive care measures and in conjunction with immunoglobulins and plasma exchange, depending on severity of GBS.¹

Peripheral Neuropathy

• Peripheral neuropathy occurred following treatment with CARVYKTI.
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, peripheral neuropathy occurred in 7% (21/285), including Grade ≥3 in 1% (3/285) of the patients.¹
• Peripheral neuropathies occurred in 7% of patients in CARTITUDE-4 (0.5% Grade 3 to 4) and in 7% of patients in CARTITUDE-1 (2% Grade 3 to 4).¹
• The median time to onset of peripheral neuropathy was 57 days (range, 1-914 days).¹
• Peripheral neuropathy resolved in 11/21 (52%) of patients with a median time to resolution of 58 days (range, 1-215 days).¹
• The median duration of peripheral neuropathy was 149.5 days (range, 1-692 days) in all patients including those with ongoing neurologic events at the time of death or data cut off.¹
• Monitor patients for signs and symptoms of peripheral neuropathies. Patients who experience peripheral neuropathy may also experience cranial nerve palsies or GBS.¹

Cranial Nerve Palsies

• Cranial nerve palsies occurred following treatment with CARVYKTI.
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, cranial nerve palsies occurred in 7% (19/285), including grade ≥3 in 1% (1/285) of the patients.¹
• Cranial nerve palsies occurred in 9% of patients in CARTITUDE-4 (Grade 3 to 4, 1%) and in 3% of patients in CARTITUDE-1 (Grade 3 to 4, 1%).¹
• The median time to onset of cranial nerve palsies was 21 days (range, 17-101 days).¹
• Cranial nerve palsies resolved in 17 of 19 (89%) of patients with a median time to resolution of 66 days (range, 1-209 days).¹
• The median duration of cranial nerve palsies was 70 days (range, 1-262) in all patients including those with ongoing neurologic events at the time of death or data cut off.¹
• The most frequent cranial nerve affected was the 7^th cranial nerve. Additionally, cranial nerves III, V, and VI have been reported to be affected.¹
• Monitor patients for signs and symptoms of cranial nerve palsies. Consider management with systemic corticosteroids, depending on the severity and progression of signs and symptoms.¹

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, HLH/MAS occurred in 1% (3/285) of patients.¹
• All events of HLH/MAS had onset within 99 days of receiving CARVYKTI, with a median onset of 10 days (range, 8-99 days) and all occurred in the setting of ongoing or worsening CRS.¹
• The manifestations of HLH/MAS include hyperferritinemia, hypotension, hypoxia with diffuse alveolar damage, coagulopathy and hemorrhage, cytopenia and multi-organ dysfunction, including renal dysfunction and respiratory failure.¹
• Patients who develop HLH/MAS have an increased risk of severe bleeding. Monitor hematological parameters in patients with HLH/MAS and transfuse per institutional guidelines.¹
• Fatal cases of HLH/MAS occurred following treatment with CARVYKTI.¹
• HLH is a life-threatening condition with a high mortality rate if not recognized and treated early. Treatment of HLH/MAS should be administered per institutional standards.¹

Prolonged and Recurrent Cytopenias

• Patients may exhibit prolonged and recurrent cytopenias following lymphodepleting chemotherapy and CARVYKTI infusion.¹
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, Grade 3 or higher cytopenias not resolved by day 30 following CARVYKTI infusion occurred in 62% (176/285) of the patients and included thrombocytopenia 33% (94/285), neutropenia 27% (76/285), lymphopenia 24% (67/285) and anemia 2% (6/285).¹
• After Day 60 following CARVYKTI infusion 22%, 20%, 5%, and 6% of patients had a recurrence of Grade 3 or 4 lymphopenia, neutropenia, thrombocytopenia, and anemia respectively, after initial recovery of their Grade 3 or 4 cytopenia.¹
• Seventy-seven percent (219/285) of patients had one, two or three or more recurrences of Grade 3 or 4 cytopenias after initial recovery of Grade 3 or 4 cytopenia. Sixteen and 25 patients had Grade 3 or 4 neutropenia and thrombocytopenia, respectively, at the time of death.¹
• Monitor blood counts prior to and after CARVYKTI infusion. Manage cytopenias with growth factors and blood product transfusion support according to local institutional guidelines.¹

Infections

• CARVYKTI should not be administered to patients with active infection or inflammatory disorders. Severe, life-threatening, or fatal infections, occurred in patients after CARVYKTI infusion.¹
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, infections occurred in 57% (163/285), including grade ≥3 in 24% (69/285) of patients.¹
• Grade 3 or 4 infections with an unspecified pathogen occurred in 12%, viral infections in 6%, bacterial infections in 5%, and fungal infections in 1% of patients. Overall, 5% (13/285) of patients had Grade 5 infections, 2.5% of which were due to COVID-19. Patients treated with CARVYKTI had an increased rate of fatal COVID-19 infections compared to the standard therapy arm.¹
• Febrile neutropenia was observed in 5% of patients after CARVYKTI infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids and other supportive care, as medically indicated.¹
• Monitor patients for signs and symptoms of infection before and after CARVYKTI infusion and treat patients appropriately. Administer prophylactic, pre-emptive and/or therapeutic antimicrobials according to the standard institutional guidelines.¹
• Counsel patients on the importance of prevention measures. Follow institutional guidelines for the vaccination and management of immunocompromised patients with COVID-19.¹

Viral Reactivation

• Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients with hypogammaglobulinemia.¹
• Perform screening for cytomegalovirus (CMV), HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) or any other infectious agents if clinically indicated in accordance with clinical guidelines before collection of cells for manufacturing.¹
• Consider antiviral therapy to prevent viral reactivation per local institutional guidelines/clinical practice.¹

Hypogammaglobulinemia

• Hypogammaglobulinemia can occur in patients receiving treatment with CARVYKTI.
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, hypogammaglobulinemia AE was reported in 36% (102/285) of patients; laboratory immunoglobulin G (IgG) levels fell below 500 mg/dL after infusion in 93% (265/285) of patients.¹
• Monitor immunoglobulin levels after treatment with CARVYKTI and administer IVIG for IgG <400 mg/dL. Manage per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.¹

Hypersensitivity Reactions

• Hypersensitivity reactions occurred following treatment with CARVYKTI. Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, hypersensitivity reactions occurred in 5% (13/285), all of which were grade ≤2. Manifestations of hypersensitivity reactions included flushing, chest discomfort, tachycardia, wheezing, tremor, burning sensation, non-cardiac chest pain, and pyrexia.¹
• Serious hypersensitivity reactions, including anaphylaxis, may be due to the dimethyl sulfoxide (DMSO) in CARVYKTI. Patients should be carefully monitored for 2 hours after infusion for signs and symptoms of severe reaction. Treat promptly and manage patients appropriately according to the severity of the hypersensitivity reaction.¹

Secondary Malignancies

• Patients treated with CARVYKTI may develop secondary malignancies.¹
• Among patients receiving CARVYKTI in the CARTITUDE-1 and CARTITUDE-4 studies, myeloid neoplasms occurred in 5% (13/285) of patients (9 cases of myelodysplastic syndrome, 3 cases of acute myeloid leukemia, and 1 case of myelodysplastic syndrome followed by acute myeloid leukemia).¹
• The median time to onset of myeloid neoplasms was 447 days (range, 56-870 days) after treatment with CARVYKTI.¹
• T-cell malignancies have occurred following treatment of hematologic malignancies with BCMA- and CD19-directed genetically modified autologous T-cell immunotherapies, including CARVYKTI. Mature T-cell malignancies, including chimeric antigen receptor (CAR)-positive tumors, may present as soon as weeks following infusions, and may include fatal outcomes.¹
• Monitor life-long for secondary malignancies. In the event that a secondary malignancy occurs, contact Janssen Biotech, Inc. at 1800526-7736 for reporting and to obtain instructions on collection of patient samples.¹

CLINICAL DATA - cartitude-1 - PHASE 1B/2 STUDY

CARTITUDE-1 (MMY2001; clinicaltrials.gov identifier: NCT03548207) was a phase 1b/2, open-label, single-arm, multicenter study that evaluated the safety and efficacy of CARVYKTI in patients with RRMM who had previously received a PI, an immunomodulatory agent, and an antiCD38 antibody. The combined analysis from the phase 1b/2 portions of the CARTITUDE-1 study evaluated the safety and efficacy of CARVYKTI in 97 patients with RRMM.^2-4

Study Design/Methods

• The study design is presented in Figure: CARTITUDE-1 Study Design.
• Primary endpoints for phase 1b: evaluate the safety and confirm the recommended phase 2 dose.³
• Primary endpoint for phase 2: evaluate the efficacy of CARVYKTI by overall response rate (ORR).³

• Per study protocol:
  • Patients were monitored during the post-infusion period (day 1-100 after administration of CARVYKTI) for safety and disease assessments including monitoring for CRS, tumor lysis syndrome, cytopenias, infections, hypogammaglobulinemia and neurologic toxicities. Patients were asked to check their temperature at least twice daily for 28 days and instructed to report any fever (≥100.4°F or ≥38°C) to the study doctor immediately to initiate monitoring for development of CRS. Secondary primary malignancies (SPMs) were to be followed from the time of signing of informed consent form to study completion.²
  • The first 6 patients enrolled in the study were hospitalized for at least 2 weeks after receiving an infusion of CARVYKTI and were asked to remain within 1-hour travel time of the hospital and in the company of a competent adult at all times for 1 additional week after discharge. Patients who were not hospitalized were asked to remain within 1-hour travel time of the study site and in the company of a competent adult (in case of occurrence of a serious adverse event, SAE) at all times for 2 weeks after receiving CARVYKTI.²
  • Patients were also monitored during the post-treatment period (day 101 until study completion) for safety and disease assessments every 28 days. Disease evaluation was to be performed until confirmed disease progression, death, start of new anticancer treatment, withdrawal of consent for study participation, or end of study (whichever occurs first).²

CLINICAL DATA - cartitude-4 - PHASE 3 STUDY

CARTITUDE-4 (MMY3002; clinicaltrials.gov identifier: NCT04181827) is a phase 3, randomized, open-label study evaluating the efficacy and safety of CARVYKTI versus standard care (physician's choice of PVd or DPd) in adult patients with lenalidomide-refractory MM after 1-3 prior LOT.^5,6

Study Design/Methods

• The study design is shown in Figure: CARTITUDE-4 Study Design.

• Per study protocol:
  • Patients were closely monitored during the post-infusion period (day 1-112 after administration of CARVYKTI) for safety and disease assessments including CRS, neurotoxicity or other clinically significant events. SPMs were to be monitored continuously from randomization.⁷
  • Patients were asked to check their temperature at least twice daily (entering 2 temperatures including their maximum daily temperature on the provided diary) during the first 28 days after infusion and were instructed to report any fever (≥38 °C or ≥100.4°F) to the investigator immediately to initiate monitoring for development of CRS.⁷
  • At the Investigator’s discretion and patient’s willingness, the patient was to be admitted for inpatient monitoring from the day of infusion (day 1) through day 14 of CARVYKTI infusion (with potential discharge on day 10 if there are no CRS, neurotoxicity or other clinically significant events), or was to receive CARVYKTI infusion as an outpatient in close proximity (within 30 min) to the hospital, be monitored for outpatient follow-up and then be admitted for the required inpatient monitoring from day 5 to day 14 after CARVYKTI infusion (with potential discharge on day 10 if there are no CRS, neurotoxicity or other clinically significant events).⁷
  • Patients were asked to remain within 1 hour of the hospital and in the company of a competent adult at all times for 1 additional week after hospital discharge or until Study day 21, whichever occurred sooner.⁷
  • Patients were also monitored during the post-treatment period (once the post-infusion follow-up is complete on day 112 to the end of the study [defined until approximately 250 deaths have occurred]) for safety and disease assessments every 28 days.⁷
  • Patients were monitored for efficacy until confirmed progressive disease (PD), death, or withdrawal of consent. After confirmed PD, patients were followed for survival, subsequent anti-myeloma therapies, response to subsequent anti-myeloma therapies including the date of subsequent progression, and SPMs every 16 weeks until the end of study. The occurrence of SPMs must have been reported during the post-infusion and post-treatment follow-up and continue until the end of the study.⁷

Literature search

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 08 April 2024.